Liquid absorbable copolymers for parenteral applications

ABSTRACT

A sustained release parenteral composition comprising an admixture of at least one drug to be delivered in a therapeutically effective amount and a bioabsorbable lactone polymer containing one or more lactone monomers that is a liquid at body temperature, provided in an amount effective to sustain or extend the release rate of the drug and a method for administering said composition to an animal.

This is a division of application Ser. No. 08/094,823, filed Jul. 20,1993 and now abandoned and, which is hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to the use of absorbable liquid lactonecopolymers for the parenteral administration of drugs. Morespecifically, it relates to the use of liquid lactone copolymers inparenteral applications for sustained or extended drug delivery.

BACKGROUND OF THE INVENTION

Pharmaceuticals are commonly administered parenterally in isotonicsolutions. However, this dosage form is not always well suited for alldrugs or prolonged drug therapies. To overcome these and other shortcomings of this dosage form several new injectable dosage formulationshave recently been developed.

The most notable recent development has been the use of bioerodible orbioabsorbable polymers in injectable dosage formulations. Severalpublications describe these new injectable dosage formulations such asU.S. Pat. No. 3,982,537 and U.S. Pat. No. 4,054,138 issued to Bucalo,U.S. Pat. No. 4,938,763 issued to Dunn et al. and "Biodegradable blockcopolymer matrices for long-acting contraceptives with constant release"J. Contr. Rel. 32. (1992) 3-14 by Z. W. Gu et al. Each of thesepublications presents a different formulation that may one day replaceconventional parenteral formulations.

Bucalo describes the use of low melting hydrogenated vegetable oils andfats as injectable in-situ implants or injectable microspheres. Theimplants are formed from vegetable oil or fat that is melted and mixedwith a drug. The mixture is then either injected into the patient wherethe mixture will solidify to form an in-situ implant, or formed intomicrospheres that are injected. Although this formulation may work forsome drugs, the heat necessary to form the liquid mixture of oil or fatand drug will in many cases inactivate or modify the drug beingadministered.

Dunn et al. describes a different biodegradable in-situ implant thatdoes not require the formulation to be heated. Dunn proposes the use ofa liquid polymer carrier that solidifies in-situ by crosslinking orprecipitation due to solvent dissipation. Although, Dunn avoids the heatinactivation problems inherent with Bucalo's implants, Dunn'sformulations also have significant short comings. The polymer systemdescribed by Dunn et al. is based on DL-lactide or L-lactide andε-caprolactone copolymers. The copolymers are used as prepolymers, whichwill be derivatized and crosslinked in-situ or dissolved in a solvent.Unfortunately, the crosslinking process requires formulation and mixingof the injectable immediately before administration, which is generallynot practical. The solvent based implants, although easier toadminister, cannot readily be used because the solvents necessary todissolve the ε-caprolactone based copolymers that Dunn describe aretoxic.

Gu and coworkers describes a formulation containing hard microspheres ofa triblock copolymer, namelypoly(ε-caprolactone-b-D,L-lactide-b-glycolide) for the controlledrelease of contraceptives. The microspheres that Gu describe aredesigned to be injected, thereby avoiding the need to surgically implanta solid dosage. Unfortunately, the kinetics of the pharmaceuticalrelease from these microspheres are complicated by the different releasemechanisms of the individual blocks of the triblock copolymer. Althoughthe complicated release mechanism is not an insurmountable obstacle tothe use of Gu's microspheres, it makes formulation of sustained releaseinjectables quite difficult.

Thus it would be a significant contribution to the art to provide aninjectable dosage form that is easy to administer and provides sustainedor extended drug release.

SUMMARY OF THE INVENTION

In one aspect, we have discovered a parenteral composition for injectionsubcutaneously or intramuscularly into animals comprising an admixtureof at least one drug to be delivered in a therapeutically effectiveamount and a bioabsorbable lactone copolymer containing two or morelactone comonomers that is a liquid at body temperature, provided in anamount effective to sustain or extend the release rate of the drug.

In another aspect of the present invention there is provided a methodfor parenterally administering a drug subcutaneously or intramuscularlyinto animals comprising injecting a composition comprising an admixtureof a therapeutic amount of at least one drug and a bioabsorbable lactonecopolymer containing two or more lactone comonomers that is a liquid atbody temperature, provided in an amount effective to sustain or extendthe release rate of the drug.

These and other objects and advantages of this invention will beapparent from the disclosure and claims provided herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 graphically illustrates the in vitro release at ambienttemperature of tolmetin over time at pH 5.65 and pH 3.85 from a randomcopolymer of ε-caprolactone and 1,4-dioxanone. The release profile at pH5.65 is represented by the squares; the release profile at pH 3.85 isrepresented by the crosses.

FIG. 2 graphically illustrates the in vitro release at 37° C. ofofloxacin over time at pH 7 in the liquid lactone copolymers produced inExamples 1, 2 and 3. The release profiles of ofloxacin from thecopolymers produced in Examples 1, 2 and 3 are represented respectivelyby the open squares, the asterisks and the crosses.

FIG. 3 graphically illustrates the in vitro release at 37° C. ofofloxacin over time at pH 7 in various concentrations from the liquidlactone copolymer prepared in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new parenteral dosage formulation foradministering to animals subcutaneously or intramuscularly a therapeuticamount of a drug in a sustained or extended release dosage form. Thisdosage form may be used in a variety of animals including domesticanimals such as dogs, cats, cattle, sheep, horses and primates(including humans).

Many nontoxic bioabsorbable homopolymers, copolymers and terpolymers,that are fluids at body temperature, may be used as a sustained orextended release carrier for intramuscular or subcutaneous injectables.In particular, there are many lactone polymers (including polymers whichcontain two or more monomers) composed of one or more lactone monomersselected from the group consisting of glycolide, L-lactide, D,L-lactide,1,4-dioxanone, ε-caprolactone, 1,5-dioxepan-2-one and trimethylenecarbonate and other commonly used lactone monomers that are fluids atbody temperature. These polymers may be linear, branched, or starbranched; statistically random copolymers or terpolymers; segmentedblock copolymers or terpolymers. Examples of suitable terpolymers areterpolymers containing comonomer combinations selected from the groupconsisting of glycolide, L-lactide, and p-dioxanone; glycolide,ε-caprolactone and p-dioxanone; and L-lactide, ε-caprolactone andp-dioxanone. These polymers should be purified to remove unreactedmonomer which may cause an inflammatory reaction in tissue.

Preferred polymers for use as sustained or extended release carriers arelactone polymers selected from the group consisting ofpoly(lactide-co-ε-caprolactone), poly(lactide-co-p-dioxanone),poly(lactide-co-1,5-dioxepan-2-one), poly(ε-caprolactone-co-p-dioxanone)and poly(1,5-dioxepan-2-one-co-p-dioxanone). The comonomer ratios ofthese copolymers should be in the range of from about 70:30 mole percentto about 30:70 mole percent and preferably in the range of from 40:60mole percent to 60:40 mole percent of the first monomer to secondmonomer. Most preferably these polymers will be random copolymers.

The copolymer carriers of this invention are characterized by beingliquids at body temperature (37° C.) and preferably being liquids atroom temperature (being liquids at 25° C.) in the absence of solvents orthe like. The copolymers of the present invention should have aninherent viscosity as determined in a 0.1 g/dL solution ofhexafluoroisopropanol (HFIP) at 25° C. ranging from about 0.05 to about0.8, dL/g preferably from about 0.05 to about 0.3 dL/g and mostpreferably from 0.05 to 0.2 gL/g. A copolymer with an inherent viscositybelow 0.05 may fail to significantly impart a controlled release profileto a pharmaceutical, and a carrier copolymer with an inherent viscosityabove 0.8 dL/g may be too viscous to be easily administered.

The variety of different therapeutic agents which can be used inconjunction with the copolymers of the invention is vast. In general,therapeutic agents which may be administered via the pharmaceuticalcompositions of the invention include, without limitation:antiinfectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelmintics; antiarthritics;antiasthmatic agents; anticonvulsants; antidepressants; antidiureticagents; antidiarrheals; antihistamines; antiinflammatory agents;antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics,antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including calcium channelblockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers; and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins. Suitable pharmaceuticals for parenteral administration arewell known as is exemplified by the Handbook on Injectable Drugs, 6thedition, by Lawrence A. Trissel, American Society of HospitalPharmacists, Bethesda, Md., 1990 (hereby incorporated by reference).

Parenteral administration of a composition of the invention can beaffected by either subcutaneous or intramuscular injection. Parenteralformulations of the copolymer may be formulated by mixing one or moretherapeutic agents with a liquid copolymer. The therapeutic agent, maybe present as a liquid, a finely divided solid, or any other appropriatephysical form. Typically, but optionally, the compositions include oneor more parenteral additives, e.g., nontoxic auxiliary substances suchas diluents, carriers, excipients, stabilizers or the like. Othersuitable parenteral additives may be formulated with the copolymer andpharmaceutically active agent or compound, however, if water is to beused it should be added immediately before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001% to about 70%, more typically about0.001% to about 50%, most typically about 0.001% to about 20% by weightof the total composition being common.

The quantity and type of copolymers incorporated into the parenteralwill vary depending on the release profile desired and the amount ofdrug employed. For a more viscous composition, generally a highermolecular weight polymer is used. If a less viscous composition isdesired, a lower molecular weight polymer can be employed. The productmay contain blends of liquid copolymers to provide the desired releaseprofile or consistency to a given formulation.

The copolymers, upon contact with body fluids including blood or thelike, undergoes gradual degradation (mainly through hydrolysis) withconcomitant release of the dispersed drug for a sustained or extendedperiod (as compared to the release from an isotonic saline solution).This can result in prolonged delivery (over, say 1 to 2,000 hours,preferably 2 to 800 hours) of effective amounts (say, 0.0001 mg/kg/hourto 10 mg/kg/hour) of the drug. This dosage form can be administered asis necessary depending on the subject being treated, the severity of theaffliction, the judgment of the prescribing physician, and the like.

Individual formulations of drugs and lactone copolymers may be tested inappropriate in vitro and in vivo models to achieve the desired drugrelease profiles. For example, a drug could be formulated with a liquidcopolymer and injected into an animal. The drug release profile couldthen be monitored by appropriate means such as, by taking blood samplesat specific times and assaying the samples for drug concentration.Following this or similar procedures, those skilled in the art will beable to formulate a variety of sustained release parenteralformulations.

The following examples illustrate, but are not intended to limit, thescope of the claimed invention.

EXAMPLE 1 Copolymerization of 1,4-Dioxanone and L-Lactide 59:41(mol/mol) 1,4-Dioxanone:L-Lactide Initial Composition

A flame dried, 500 mL, single neck round bottom flask was charged with150.0 grams (1.47 mol) of 1,4-dioxanone, 150.0 grams (1.04 mol) ofL-lactide, 60.0 grams (0.65 mol) of glycerol, and 0.25 mL (0.75 mmol) ofa 0.33M solution of stannous octoate in toluene. The flask was fittedwith a flame dried mechanical stirrer. The reactor flask was flushedwith dry nitrogen gas, and an inert atmosphere was maintained throughoutthe reaction. The reaction mixture was heated to 110° C. for 74 hours.The copolymer was a viscous liquid at room temperature and was vacuumdried at 80° C. for three days (0.1 mm Hg) to remove any unreactedmonomers. The copolymer had an inherent viscosity of 0.16 dL/g inhexafluoroisopropanol (HFIP) at 25° C. (c=0.10 g/dL). The copolymer wasthen extracted with ether for 35 hours using a liquid-liquid extractor.The ether layer was decanted off and the liquid absorbable copolymer wasvacuum dried at 60° C. for seven days. The copolymer composition wasmeasured by 300 MHz ¹ H NMR spectroscopy and found to be 36.9 molepercent poly[L-lactide] repeating units, 49.5 mole percentpoly[1,4-dioxanone] repeating units, 1.7 mole percent residual1,4-dioxanone, and 11.9 mole percent unreacted glycerol. This copolymerwill be abbreviated as 59:41 PDO:LL.

EXAMPLE 2 Copolymerization of ε-Caprolactone and 1,4-Dioxanone 60:40(mol/mol) ε-Caprolactone:1,4-Dioxanone Initial Composition

A flame dried, 250 mL, single neck round bottom flask was charged with68.5 grams (600 mmol) of vacuum distilled ε-caprolactone, 40.8 grams(400 mmol) of 1,4-dioxanone, 3.7 milliliters (49 mmol) of propyleneglycol (USP grade), and 0.12 milliliters (40 μmol) of a 0.33M stannousoctoate solution in toluene. The flask was fitted with a flame driedmechanical stirrer. The reactor flask was flushed with dry nitrogen gas,and an inert atmosphere was maintained throughout the reaction. Thereaction mixture was heated to 160° C. for 24 hours, and then, thereaction temperature was reduced to 110° C. and held there for about 24hours. The copolymer was a viscous liquid at room temperature and wasvacuum dried at 80° C. for about 80 hours (0.1 mm Hg) to remove anyunreacted monomers. The copolymer had an inherent viscosity of 0.19 dL/gin hexafluoroisopropanol at 25° C. (c=0.10 g/dL). The liquid copolymerexhibited a Brookfield viscosity of 7,620 cps at 25° C. The weightaverage molecular weight (M_(w)) was 3230 daltons and the number averagemolecular weight (M_(n)) was 1990 daltons as determined by gelpermeation chromatography (GPC) using poly[methyl methacrylate]standards. The copolymer composition was measured by 300 MHz ¹ H NMRspectroscopy and found to be 64.6 mole percent poly[ε-caprolactone]repeating units, 32.6 mole percent poly[1,4-dioxanone] repeating units,and 2.8 mole percent residual 1,4-dioxanone. This copolymer will beabbreviated as 60:40 CL:PDO.

EXAMPLE 3 Copolymerization of ε-Caprolactone and 1,4-Dioxanone 50:50(mol/mol) ε-Caprolactone:1,4-Dioxanone Initial Composition

The procedure of Example 2 was essentially repeated except that thereaction flask was charged with 57.0 grams (500 mmol) of vacuumdistilled ε-caprolactone, 51.0 grams (500 mmol) of 1,4-dioxanone, 3.7milliliters (49 mmol) of propylene glycol (USP grade), and 0.12milliliters (40 μmol) of a 0.33M stannous octoate solution in toluene.In addition, the copolymerization was conducted at 140° C. for 24 hours.The copolymer was a viscous liquid at room temperature and had aninherent viscosity of 0.22 dL/g in HFIP at 25° C. (c=0.10 g/dL). Thecopolymer had a Brookfield viscosity of 11,200 cps at 25° C. The M_(w)was 3290 daltons and the M_(n) was 1850 daltons as determined by GPC.This copolymer will be abbreviated as 50:50 CL:PDO.

EXAMPLE 4 Copolymerization of ε-Caprolactone and 1,4-Dioxanone 40:60(mol/mol) ε-Caprolactone:1,4-Dioxanone Initial Composition

The procedure of Example 2 was essentially repeated except that thereaction flask was charged with 45.7 grams (400 mmol) of vacuumdistilled ε-caprolactone, 61.3 grams (600 mmol) of 1,4-dioxanone, 3.7milliliters (49 mmol) of propylene glycol (USP grade), and 0.12milliliters (40 μmol) of a 0.33M stannous octoate solution in toluene.The copolymer was a viscous liquid at room temperature and had aninherent viscosity of 0.18 dL/g in HFIP at 25° C. (c=0.10 g/dL). Thiscopolymer had a Brookfield viscosity of 11,700 cps at 25° C. The M_(w)was 2960 daltons and the M_(n) was 1720 daltons as determined by GPC.The copolymer composition was measured by 300 MHz ¹ H NMR spectroscopyand found to be 48.8 mole percent poly[ε-caprolactone] repeating units,47.8 mole percent poly[1,4-dioxanone] repeating units, and 3.4 molepercent residual 1,4-dioxanone. This copolymer will be abbreviated as40:60 CL:PDO.

EXAMPLE 5 In Vivo Absorption and Tissue Reaction

The liquid copolymers of ε-caprolactone and 1,4-dioxanone prepared inExamples 2, 3, and 4 were sterilized by filtration and injected into thesubcutis and gluteal muscles of rats to observe the absorption andtissue reaction of these liquid copolymers.

Thirty rats were routinely anesthetized, and the skin over the glutealmuscles was prepared for sterile surgery. An incision was made on thedorsal midline over the lumbosacral region, and the gluteal muscles wereexposed. For each liquid copolymer, a syringe with a 16 gauge needle wasused to inject 60 μL of copolymer into each gluteal muscle, and asyringe with an 18 gauge needle was used to inject 300 μL of copolymerinto the subcutaneous tissue on the flank. Each rat received twodifferent copolymers: one in the right gluteal muscle and flank, andanother one on the left side. Six rats were humanely killed after 1, 3,7, 14, and 56 days postoperatively. This procedure allowed evaluation offour subcutaneous and four intramuscular sites for each copolymer eachtime period. The subcutaneous sites were grossly evaluated for residualcopolymer, and histologic sections were evaluated tissue reaction andresidual copolymer.

The tissue reaction was minimal to slight at all of the time periods foreach copolymer. The implants were still intact after being implanted for56 days, but they were reduced in size. As expected, the copolymer withthe highest proportion of ε-caprolactone (Example 2) was the leastabsorbed at 56 days.

Absorption was more difficult to measure, but the diameters of all ofthe subcutaneous implants were about one fourth to one third theiroriginal length after 56 days of implantation, implying that thecopolymers had been absorbed substantially.

EXAMPLE 6 Liquid Copolymers for Drug Delivery

To demonstrate the use of these liquid copolymers as drug releasevehicles, tolmetin was dissolved in a 50:50 (mol/mol) random copolymerof ε-caprolactone and 1,4-dioxanone synthesized as described in Example2, and the resulting viscous liquid was suspended in two acetate buffersof different pH. The concentration of tolmetin that was released intothe buffer over time was monitored by ultraviolet spectroscopy. Theresults of these experiments are shown in FIG. 1 as a plot of thepercent of the maximum release of tolmetin versus time in vitro. Asexpected, the release of tolmetin was slower in the more acidic medium,because the rate of the neutralization reaction between the carboxylgroup of tolmetin and the acetate anion in the buffer decreases withdecreasing pH. These data show that liquid absorbable copolymers can beused as drug delivery reservoirs. The exact release profile will dependon the chemical properties of the drug (e.g., solubility, partitioncoefficients, chemical reaction rates, etc.) and on the experimentalconditions (buffer type, pH, and ionic strength in the in vitroexperiments and the types of biochemical and cellular reactions in thein vivo experiments that vary from tissue to tissue).

EXAMPLE 7 In Vitro Release Kinetics of d,l-Ofloxacin from LiquidAbsorbable Copolymers

Suspensions of d,l-ofloxacin in liquid absorbable copolymers wereprepared by blending 30 milligrams of d,l -ofloxacin powder into 3.00grams of liquid copolymer by stirring the mixture with a spatula atambient temperature until the mixture appeared to be homogeneous,producing suspensions containing 1% d,l-ofloxacin by weight.Approximately 200 milligrams of these suspensions were transferred intoopen-top cylindrical aluminum cups having diameters of 12 millimetersand heights of 5 millimeters. The cups containing the suspensions ofcopolymer and drug were carefully submerged in a glass vial containing25 mL of phosphate buffered saline (PBS), pH 7.0. The aluminum cupsconstrained all of the test samples into a disk geometry having adiameter of 12 millimeters and an initial thickness of 2 millimeterswith one face of the disk in contact with the PBS. The glass vials weresealed with rubber closures and then transferred to a water bath set at37° C. The samples were continuously agitated by a gentle sinusoidalreciprocating motion having an amplitude of 3.5 cm and a frequency ofapproximately 1 sec⁻¹. At predetermined intervals, 200 μL of PBS wasremoved and analyzed by high pressure liquid chromatography for d,l-ofloxacin content. FIG. 2 shows the in vitro release profile ofd,l-ofloxacin over a three day period. The fraction of the initialamount of d,l-ofloxacin measured in the PBS was plotted against time forthree different liquid copolymer suspensions. The three different liquidabsorbable copolymers used in this study were those prepared in Examples1, 2, and 3.

As illustrated in FIG. 2, the release profile of d,l-ofloxacin dependedsignificantly on the composition of the liquid copolymer in which it wassuspended. In general, this dependence of the drug release profile onthe composition of the liquid copolymer can be exploited in the field ofinjectable drug delivery systems. These drug suspensions or solutions inliquid absorbable copolymers can be injected directly into the tissue ofinterest, and the rate at which the drug is released can be controlledby the proper choice of the liquid copolymer.

EXAMPLE 8 Loading Effects on the Release Profile of d,l-Ofloxacin

Suspensions of d,l-ofloxacin in a 50:50 (mol/mol) random copolymer of1,4-dioxanone and L-lactide (see Example 1) were prepared by blending30, 60, and 150 milligrams of d,l-ofloxacin powder into 3.00 grams ofliquid copolymer by stirring the mixture with a spatula until themixture was homogeneous, producing suspensions that contained 1, 2, and5 percent d,l-ofloxacin by weight. The amount of d,l-ofloxacin releasedinto PBS at 37° C. was determined using the method described in Example7. FIG. 3 shows the release profile of d,l-ofloxacin for the threedifferent drug loadings. Clearly, the release profile, reported as thefraction of the total amount of d,l -ofloxacin that was detected in thePBS after a given time, was not dependent on the drug loading within thenarrow range of one to five weight percent. However, the release profileof d,l-ofloxacin may show a strong dependence on drug loading whenanother type of liquid copolymer is employed. In general, the dependenceof the drug release profile on loading and dose can be measuredexperimentally by one skilled in the art.

We claim:
 1. A parenteral composition for injection subcutaneously orintramuscularly into animals of at least one drug consisting essentiallyof an admixture of at least one drug to be delivered in atherapeutically effective amount; and a bioabsorbable lactone terpolymerhaving three or more lactone monomers that is a liquid at bodytemperature, provided in an amount effective to sustain or extend therelease rate of the drug, wherein the inherent viscosity of theterpolymer is between about 0.05 dL/g and about 0.8 dL/g as determinedin a 0.1 g/dL solution of hexafluoroisopropanol at 25° C. and thelactone terpolymer contains substantially no unreacted monomer.
 2. Theparenteral composition of claim 1 wherein the terpolymer is composed ofthree or more lactone monomers selected from the group consisting ofglycolide, L-lactide, D,L-lactide, 1,4-dioxanone, ε-caprolactone,1,5-dioxepan-2-one and trimethylene carbonate.
 3. The parenteralcomposition of claim 2 wherein the terpolymers are liquids at 25° C. 4.The parenteral composition of claim 1 wherein the terpolymer is a threemonomer combination selected from the group consisting of glycolide,L-lactide, and 1,4-dioxanone; glycolide, ε-caprolactone and1,4-dioxanone; and L-lactide, ε-caprolactone and 1,4-dioxanone.